Alzheimer's disease (AD) is a progressive and untimely fetal dementia. Its cause is not yet known, but a correlation exists with synaptic pathology, which may be responsible for cognitive deterioration. We, and recently others, have proposed that synaptic pathology in AD is caused by synaptically active Abeta oligomers, which we have called ADDLs. The oligomer hypothesis is supported by compelling evidence from multiple laboratories. The evidence, however, comes almost exclusively from studies with model systems and investigator-generated oligomers. Need addressed by this proposal: A major concern is whether experimental evidence that favors the ADDL hypothesis is clinically relevant. This study therefore is designed to determine the level of occurrence and toxicology of ADDLs in human samples. AIM 1: Quantify ADDL occurrence in human subjects AD. We will determine the structural forms of ADDLs that are present, their distribution in situ, and their abundance in brain, CSF, and plasma. AIM 2: Evaluate the CNS toxicology of human ADDLs. We will determine where ADDL binding sites are found in relation to synapses in rat hippocampus culture models and test the prediction that binding of human ADDLs causes synaptic pathology. To characterize human ADDLs, we have developed sensitive ADDL antibodies and immunoassays. Proposed experiments will extend preliminary findings that indicate (i) ADDLs are present in human cortex and increase as much as 70-fold in AD (ii) ADDLs act extracellularly and bind to plasma membranes at particular post-synaptic terminals (iii) Synaptically-bound ADDLs alter synapse homeostasis, causing aberrant growth of pre- and post-synaptic terminals and the formation of ectopic dendritic spines. This study will provide the first clinically relevant evaluation of the ADDL hypothesis. In addition to testing a series of key predictions, it lays a foundation for two future goals: (1) To test the degree of correlation between dementia and ADDLs in a large group of subjects, including those with mild cognitive impairment (MCI) and early to middle-level AD; (2) To develop new approaches to Alzheimer's therapeutics and diagnostics using ADDLs as optimal targets.